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Review Article |
Endocrinology, Diabetes and Metabolism Section, Medical Service, VA Medical Center, and Department of Internal Medicine (Endocrinology and Metabolism), Louisiana State University School of Medicine at Shreveport, Shreveport, Louisianna
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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Key words: zinc, diabetes, insulin, antioxidants
Key teaching points:
• Zinc plays a key role in the synthesis and action of insulin, both physiologically and in the pathologic state of diabetes.
• Hyperglycemia from either Type 1 or Type 2 diabetes causes physiologically important losses of Zn from the body. These losses may worsen the underlying diabetes but are probably not responsible as the causal agent.
• The complications of diabetes may be mediated, at least in part, through oxidative stress and Zn plays a key role in the cellular antioxidative defense. If there is insufficient Zn, oxidative stress may damage the cell irreversibly, producing or exacerbating some of the classic complications of diabetes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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As with any communication, we must all have a common understanding of the problem and, in that regard, some basic review of diabetes mellitus is in order. It is not true that diabetes is diabetes is diabetes. There are several forms of disordered glucose metabolism which are referred to collectively as diabetes. While all diabetes mellitus syndromes have in common some degree of hyperglycemia, the hyperglycemia is a symptom, not the metabolic error itself. The etiologies of the different types of diabetes differ as do the treatments, so that a simple reference to diabetes is not warranted. Reviewing some of these basics is necessary, therefore, so that we have a common information base.
Type I diabetes mellitus has been called "juvenile" diabetes since it most often occurs in children and young adults, but it is clear that an individual of any age can develop this metabolic error. The current nomenclature for this form of diabetes is "Insulin Dependent Diabetes Mellitus," Type I diabetes, or IDDM. There is destruction of the beta cells of the Islets of Langerhans in the pancreas, most often on an autoimmune basis, resulting in no insulin being produced. Without insulin, muscle, fat and liver cells cannot transport glucose from the blood to the intracellular space. Intracellular starvation ensues with fats becoming the primary intracellular energy source. This form of energy generation results in the production of ketone bodies and organic acids, primarily acetoacetic and beta hydroxybutyric acids, with the consequence of the development of severe metabolic acidosis. This results in the typical picture of diabetic ketoacidosis (DKA). Without prompt intervention, particularly the administration of insulin and fluids, DKA is frequently fatal. These patients are dependent on insulin for life, not just control of the blood glucose level. In general, a dose sufficient to replace the normal production of insulin will result in acceptable normalization of the blood glucose. This is approximately 20 to 25 units per day.
The metabolic errors in Type II diabetes are markedly different from those observed in Type I diabetes. This disorder has been referred to as "adult" onset of diabetes. As is the case with Type I diabetes, this age stratification is insufficient to define differences. Type II may be seen in children and young adults, although it is uncommon. This was seen often enough, however, to have been given a name of its own: "MODY" syndrome, standing for Maturity Onset Diabetes of Youth. No matter the age, in Type II diabetes the pancreatic islet cells are capable of making large quantities of insulin, at least at the beginning of the disease. In the healthy normal individual, insulin binds to a cell membrane receptor and, through several pathways, results in the transport of glucose across the membrane. The intracellular events associated with the activation of glucose transport after the signal from the insulin-receptor complex is received are called the "post-receptor" events. To a great extent, it is the failure of the post-receptor events that results in hyperglycemia in and of itself. In response to the hyperglycemia, the pancreatic islets produce greater and greater quantities of insulin which results in a "down regulation" of the number of insulin receptors on the cell membrane, which compounds the problem. This results in both hyperglycemia and hyperinsulinemia. Additionally, the beta cells cannot make enough insulin to normalize the glucose, suggesting an error in the ability of the beta cell to synthesize insulin. As the disease progresses, there may be an exhaustion of the beta cells with a relative inability to keep up with the needs for insulin production. The resultant decrease in insulin produced results in even greater hyperglycemia. It follows that, as in Type I diabetes, hyperglycemia is the hallmark of the disease. Unlike Type I diabetes, however, in Type II diabetes there is plenty of insulin, it just doesn’t work very well, and the islets cannot produce enough insulin to compensate. There is no intracellular starvation and no ketoacidosis. In type II diabetes, oral medications can improve the cellular sensitivity to insulin and increase insulin release. If an adequate response cannot be obtained with these compounds, exogenous insulin may be required to normalize the blood glucose, but these patients are not dependent on insulin for existence as are the type I diabetics. Since these patients are resistant to insulin, the daily dose of insulin necessary to approximate normalization of the blood glucose is significantly higher than the average daily production. In these patients, therapeutic doses of insulin in addition to the endogenously produced insulin generally range from 50 to 200 units per day as compared to the 20 to 30 units per day produced by a normal individual.
Pregnancy may frequently be associated with disorders of glucose metabolism resulting in gestational diabetes. Since both hyperglycemia and hyperinsulinemia are detrimental to the fetus, very close control of the blood glucose during pregnancy is required. The underlying physiology is more complex than in Type I or Type II diabetes. Women who have had gestational diabetes may go on to become overtly diabetic after pregnancy, may never have any problem with glucose metabolism other than when pregnant, or may be "normal" for many years before developing diabetic symptoms. Because insulin is a powerful growth factor and can be produced by the fetal pancreas in response to high levels of maternal blood glucose, prolonged maternal hyperglycemia can result in macrosomia, or large/heavy for gestational age, babies, congenital fetal abnormalities and spontaneous abortion/miscarriage. Because of the serious complications associated with both the hyperglycemic and hyperinsulinemic states, the diagnostic criteria for gestational diabetes are considerably more stringent than for other forms of diabetes. A lesser degree of hyperglycemia is necessary for the diagnosis of gestational diabetes and the level of control of the hyperglycemia with exogenous insulin during pregnancy is much "tighter."
Several commonly used drugs may also result in significant hyperglycemia, sometimes called secondary diabetes. Glucocorticoids, which include prednisone, cortisone, dexamethasone and other corticosteroids, is the class most often associated with iatrogenic hyperglycemia. Other commonly used drugs include some diuretics and anti-hypertensives. In general, the hyperglycemia associated with the administration of these drugs usually disappears when the drug is discontinued. This may be called drug-induced diabetes, but it is unclear if this really should be called diabetes or differentiated as drug-induced hyperglycemia. In those in whom the drug cannot be discontinued, the hyperglycemia must be treated as if it were diabetes. This illustrates how fine the line is between the underlying pathophysiology we call diabetes and the common symptom of hyperglycemia.
Other forms of hyperglycemia and insulin resistance also exist, but are relatively rare. In some patients there are no insulin receptors or there are receptors but autoantibodies block them. In these patients there is very severe insulin resistance and the intracellular environment postreceptor events work, but because there is no signaling across the cell membrane resulting from the insulin interactions, the intracellular environment is unaware of high levels of extracellular insulin. The result resembles Type I diabetes but requires more than replacement doses of insulin. In these patients daily insulin therapeutic requirements of 500 to 1000 units per day are not uncommon.
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ZINC AND INSULIN INTERACTIONS |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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It has been known for decades that a physical chemical relationship exists between insulin and zinc. Long before there was any biochemical evidence for the relationship between zinc and insulin in the beta cell, it was clear that the addition of zinc to insulin would change the time course of the effect of a given dose of insulin. As early as the 1930s, when insulin was just becoming available for commercial use, zinc was being added in vitro to make PZI (protamine zinc insulin) and lente crystalline insulin which prolonged the duration of action of the insulin by delaying its absorption from the subcutaneous injection site thus requiring fewer insulin injections.
Only since the 1970s have the biochemical pathways and structures for insulin been known. Insulin is produced by the beta cell of the pancreatic islets as a single chain peptide that is bent around itself and linked by two inter-chain disulfide bonds. This proinsulin is cleaved by the removal of an intracellular chain fragment known as the "C-peptide" to form two peptide chain (alpha and beta) molecules of 51 amino acids cross-linked to each other by inter-chain disulfide bonds. This is the insulin monomer. In the presence of zinc within the cell, insulin monomers assemble to a dimeric form for storage and secretion as the zinc crystal. Zalewski showed in 1994 that high concentrations of glucose and other secretagogues decrease the islet cell labile Zn and video fluorescence analysis showed Zn concentrated in the islet cells was related to the synthesis, storage and secretion of insulin [1].
In vitro, in the presence of zinc and at neutral pH, dimeric insulin assembles further into a hexamer consisting of three dimeric units. This form of insulin is relatively stable and it is this hexameric crystal which is the commonly used pharmacologic form. The size of the crystal is, at least in large part, the determinant of dissolution rate. Other crystal modifications have been described, but are not in clinical use. Changes in the tertiary conformation of the hexamer may also result in significant biologically important changes relating to release rate and consequent biologic activity [2–4]. This hexamer is capable of adopting at least three conformations, the physiologic consequences of which are not known [5]. Beyond the physical chemical effects of conformation, there are data to suggest that the conformational changes also affect the receptor binding and antigenic properties of insulin. In vitro data suggest that insulin binds to isolated liver membranes to a greater extent and that there is less degradation when Zn is co-administered with insulin [6].
While it is not clear if there is any relationship to degradation or alterations in binding, it has also been suggested that antigenic determinants are altered by the removal of Zn from insulin by changing the conformation of the molecule. In one series of studies, Zn-free insulin was much less immunologically active than Zn insulin in immune hemolysis inhibition assays while there was little difference in radioimmune assay determinations. This suggests that there are several binding and activation mechanisms and at least one of them is conformational dependent [7].
Therapeutic interventions to alter the zinc insulin interactions have also been attempted. With the development of genetic "engineering," it has become possible to develop analogues of insulin which do not form Zn-insulin hexamers which result in a more rapid absorption from the injection site [8]. These, and related very rapidly acting insulins, can provide the very short pulse effects which characterize the physiologic insulin response to a meal.
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EFFECTS OF DIABETES ON ZINC METABOLISM |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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The one thing that is clear, however, is that there is loss of a large amount of zinc from the body via the urine. The source of the zinc that is excreted remains incompletely resolved. There is a concurrent hypozincemia and a decrease in tissue zinc stores, but it is not clear if this is a result of the hyperzincuria or an independent event related to the effect of insulin or hyperglycemia on loss of Zn from the tissue stores with a resultant loss of zinc to the plasma from where it is excreted with a net loss of total body zinc and eventual hypozincemia. It has been postulated that hyperglycemia interferes with the active transport of Zn back into the renal tubular cells. In dogs, at least, experimentally-induced hyperglycemia resulted in significant hyperzincuria [13]. In rats made diabetic by streptozotocin (STZ), who therefore do not have any genetic code for the metabolic defects seen in diabetes, increased zinc excretion has been routinely observed. Administration of insulin with reduction in the hyperglycemia reduces, but does not appear to completely ameliorate the hyperzincuria [14,15].
The hypothesis that the hyperglycemia and resultant glucose load presented to the kidney is responsible for the hyperzincuria is supported in humans by data showing a significant correlation between the hemoglobin Alc and urinary Zn excretion. Hemoglobin Alc is a reliable quantitative indicator of long-term hyperglycemia. In a study of 175 patients with both Type I and II diabetes, there was a positive correlation between urinary zinc excretion and hemoglobin Alc (p < 0.024) [11].
In a group of age/sex matched diabetic and normal subjects, cellular loss of zinc was documented from granulocytes as a marker for intracellular zinc status for the body in general in otherwise healthy individuals. Plasma Zn was 17% lower in the diabetic group than the control group (p < 0.0001), but intracellular Zn differences did not reach statistical significance suggesting that the renal effects may be predominant in the eventual production of total body Zn depletion in diabetes [16]. While hyperzincuria is almost uniformly found in diabetes, decreases in tissue and plasma pools are not. McNair et al [17] confirmed hyperzincuria in relationship to the degree of hyperglycemia, but not glycosuria. These studies, however, have not demonstrated hypozincemia in the presence of reproducible hyperzincuria and the authors suggest that tissue and plasma zinc losses via the urine may be ameliorated by a compensatory increase in gastrointestinal absorption of zinc. Other data, however, have suggested that there is also a defect in zinc absorption associated with hyperglycemia or diabetes. Kinlaw et al [13] demonstrated abnormal Zn tolerance tests in diabetic patients suggestive of decreased absorption. Escobar also demonstrated a down regulation of fractional Zn transport which may be related to increased production of metallothionein in diabetics. Metallothionein is an intracellular cation binding protein which appears to act as, among other things, an inhibitor of Zn transport. This decrease in gastrointestinal absorption, coupled with hyperzincuria, could account for significant loss of intracellular Zn [18].
The effects of hyperinsulinism/hyperglycemia on tissue concentrations are difficult to evaluate. Cordova et al [19] found increased tissue Zn in liver, muscle and kidney in streptozotocin diabetic rats. These are the tissues that are responsive to insulin in terms of glucose transport. When the rats were exercised, which allows insulin independent glucose transport in muscle, tissue Zn decreased suggesting zinc may be lost from cells as glucose is translocated into muscle, although the linkage is far from clear [19]. Other studies also suggest that these same tissues increase zinc concentrations in the diabetic state [15,20]. Conflicting data was demonstrated in another approach to the tissue/zinc question in the spontaneous diabetic sand rat animal model. Unlike the STZ diabetes model in which there is no genetic component, these rats may have a different mechanism for cellular responses to insulin and hyperglycemia. In these animals, hyperglycemia/hyperinsulinemia was associated with reduced tissue zinc in liver, kidney and muscle. Again, it should be noted that these are tissues in which insulin affects glucose metabolism. There were no changes in bone zinc observed in this study. There was no data for other tissues such as brain, which do not require insulin for the transmembrane transport of glucose [21]. Clearly there are conflicting data which may represent interactions with alterations in other trace elements, differential effects of hyperinsulinism or hyperglycemia, or other factors not yet appreciated.
Confounding many of the human studies is the effects of concurrent medications. Serum and urinary zinc levels were evaluated in patients with diabetes, congestive heart failure and both states. No differences in serum zinc levels were observed in any group, but hyperzincuria was greater in the group with both states than with either diabetes or congestive heart failure alone. Renal function, as evaluated by serum creatinine, was not different between the groups. While loop diuretics do not seem to be related to increased Zn excretion in this study, there may be a relationship with hyperzincuria and the higher doses of ACE inhibitors used in the group with both disorders. The exact mechanism, however, remains unclear [22].
While it is clear that urinary excretion of Zn is markedly increased in individuals with diabetes, if hyperglycemia is the primary etiology, replacement with oral Zn supplementation should provide sufficient treatment. High dose supplementation in Type I diabetics and normal individuals was evaluated by serum and urine zinc and mononuclear cell Zn concentrations. Zinc excretion and mononuclear zinc concentrations increased by a similar amount in both groups. There did not appear to be any evidence for total body Zn deficiency in the diabetic group despite the clear hyperzincuria. Somewhat distressing in this study was an increase in hemoglobin Alc in all individuals which was, of course, of greater concern in the diabetic subjects. The data suggested that there is a possible Zn toxicity for high dose supplementation which has greater ramifications in diabetics. It also suggests that there is more than hyperzincuria responsible for the abnormalities in Zn metabolism in diabetic patients [23].
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EFFECTS OF ZINC ON DIABETES MELLITUS (PRIMARY DISEASE EFFECTS) |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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The etiology of Type I diabetes is the result of autoimmune attack on the beta cell with subsequent destruction of the cell. One proposed mechanism by which immune processes damage cells is through cytokine mediated induction of intracellular oxidizing agents, particularly free radicals. A similar mechanism is involved in the cell damage that occurs in the tissues associated with the "complications" of diabetes, particularly the retina in retinopathy. These oxidizing agents include free radicals, which have unpaired electrons, such as superoxide radicals (O2-), alkoxyl (RO-) and peroxyl radicals (ROO-), hydrogen peroxide (H2O2), and lipid peroxides (LOOH). Because zinc is a necessary factor in a variety of "antioxidant" enzymes, particularly superoxide dismutase, catalase and peroxidase, alterations of zinc metabolism such that adequate zinc is unavailable for these enzymes might be expected to contribute to the tissue damage observed in diabetes [27].
Because cytokines are one of the mediators of the immune response, they are potential candidates as the mediators of cell destruction in the autoimmune attack on the human beta cell which occurs in Type I diabetes. Rabinovitch et al [28] examined the relationship between cytokine induced (interleukin 1b, tumor necrotic factor (TNF) and interferon gamma) pancreatic beta cell destruction, production of malondialdehyde (MDA), an end product of lipid peroxidation, and nitrite, the end product of nitric oxide. These studies suggested cytokines are toxic to the human beta cell by producing oxygen free radicals, lipid peroxidation, and aldehyde production in the islets and that MDA was one of the cytotoxic mediators [27,28].
Other investigators have suggested that the Zn-metallothionein complex in the islet cell provides protection against free radicals produced in the cell from any cause, and certainly the immune mediated cytokine provoked oxidative stress would be a significant oxidative stress. The more depleted the intracellular Zn stores, the less able the cell is to defend itself against this oxidative load. This provides a potential mechanism for zinc deficiency to affect the progress of Type I diabetes. There is also some data suggesting that the same mechanism of intracellular oxidative load may be responsible for the streptozotocin induced experimental diabetes. Zimny et al have demonstrated induction of metallothionein production in the islet cell in response to STZ-induced OH radical production [29]. Yang and Cherian [30] demonstrated STZ-induced lipid peroxidation and decreased superoxide dismutase (SOD). The lipid peroxidation was mitigated by pretreatment with intraperitoneal Zn to induce increased production of metallothionein, although no changes in SOD were noted. Metallothionein requires Zn for activation and a paucity of Zn would exacerbate the deleterious effects of STZ on the islet cell. Roza showed marked decreases in pancreatic SOD and catalase antioxidant activity which preceded the loss of beta cell function suggesting increased beta cell vulnerability to free radical attack and cell destruction in genetically diabetic BB rats [31]. All of these data suggest a role for Zn in the protection of the beta cell against the immune-mediated free radical attack, but it is not clear if this related to the genetic factors in the predisposition to diabetes or of the islitis itself prior to cell destruction.
In Type II diabetes there is no good evidence for oxidative stress as a major factor in the development of either insulin deficiency or islet cell damage, but there is clear evidence for increased secretion of insulin, at least early in the progress of the disease. Since Zn leaves the cell with insulin, the greater secretion of insulin causes cellular depletion of Zn. The cell can make more insulin, but it cannot make more Zn and, with hyperzincuria, the Zn co-secreted is more likely to be excreted and not available for re-uptake into the cellular pool. With the slow loss of intracellular zinc, the less insulin is secreted for a given glucose level and the islet cell becomes more vulnerable to all sorts of damage. This matches the clinical picture in which, after prolonged hyperglycemia and inability of the islet cell to make enough insulin to control the glucose, there is a loss of islet cell altogether. This provides a mechanism by which Zn deficiency may affect the progress of Type II diabetes [32].
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EFFECTS OF ZINC ON DIABETES MELLITUS (SECONDARY COMPLICATIONS) |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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In mice made diabetic with STZ there was a marked increase in fetal loss and malformation as compared with nondiabetic mice. In similar, but transgenic mice for the human copper-zinc superoxide dismutase (Cu-Zn SOD), there were fewer fetal malformations than in controls without the gene suggesting SOD reduces diabetic embryopathy, presumably by reducing oxygen free radicals [33]. In other animal studies Minami et al [34] demonstrated an increase in the progression of diabetic nephropathy in STZ diabetic rats when Zn deficiency was induced either by increased renal excretion or by dietary induced deficiency.
In humans, Faure demonstrated some protective effect of Zn supplementation for the development of diabetic retinopathy associated with an increase in SOD. This suggested that the observed decrease in retinopathy may be the result of decreased lipid peroxidation of the retinal polyunsaturated fatty acids [35].
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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TOPABSTRACTINTRODUCTIONZINC AND INSULIN INTERACTIONSEFFECTS OF DIABETES ON...EFFECTS OF ZINC ON...EFFECTS OF ZINC ON...CONCLUSIONSREFERENCES |
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